One small change in a protein in 2013 could have led to surge in microcephaly
A single genetic mutation made the Zika virus far more dangerous by enhancing its ability to kill nerve cells in developing brains, a new study suggests.
The small change — which tweaks just one amino acid in a protein that helps Zika exit cells — may cause microcephaly, researchers report September 28 in Science. The mutation arose around May 2013, shortly before a Zika outbreak in French Polynesia, the researchers calculate.
Zika virus was discovered decades ago but wasn’t associated with microcephaly — a birth defect characterized by a small head and brain — until the 2015–2016 outbreak in Brazil. Women who had contracted the virus while pregnant started giving birth to babies with the condition at higher-than-usual rates (SN: 4/2/16, p. 26).
Researchers weren’t sure why microcephaly suddenly became a complication of Zika infections, says Pei-Yong Shi, a virologist at the University of Texas Medical Branch at Galveston. Maybe the virus did cause microcephaly before, scientists suggested, but at such low rates that no one noticed. Or people in South America might be more vulnerable to the virus. Perhaps their immune systems don’t know how to fight it, they have a genetic susceptibility or prior infections with dengue made Zika worse (SN: 4/29/17, p. 14). But Shi and colleagues in China thought the problem might be linked to changes in the virus itself.
Different versions of Zika virus injected directly into fetal mouse brains caused varying degrees of damage. A strain isolated in Cambodia in 2010 caused some brain cell death, resulting in a slightly smaller brain (middle) than normal (left). A mutation in the virus led to more brain cell damage and much smaller brains (right).
The researchers compared a strain of Zika isolated from a patient in Cambodia in 2010 with three Zika strains collected from patients who contracted the virus in Venezuela, Samoa and Martinique during the epidemic of 2015–2016. The team found seven differences between the Cambodian virus and the three epidemic strains.
Researchers engineered seven versions of the Cambodian virus, each with one of the epidemic strains’ mutations, and injected the viruses into fetal mouse brains. Viruses with one of these mutations, dubbed S139N, killed brain cells in fetal mice and destroyed human brain cells grown in lab dishes more aggressively than the Cambodian strain from 2010 did, the researchers found.
“That’s pretty convincing evidence that it at least plays some role in what we’re seeing now,” says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases.
The mutation changes an amino acid in a Zika protein called prM. That protein helps the virus mature within infected cells and get out of the cells to infect others. Shi and colleagues don’t yet know why tweaking the protein makes the virus kill brain cells more readily.
The alteration in that protein probably isn’t the entire reason epidemic strains cause microcephaly, Shi says. The Cambodian strain also led to the death of a few brain cells, but perhaps not enough to cause microcephaly. “We believe there are other changes in the virus that collectively enhance its virulence,” he says. In May in Nature, Shi and colleagues described a different mutation that allows the virus to infect mosquitoes more effectively.
Brain cells from different people vary in their susceptibility to Zika infections, says infectious disease researcher Scott Weaver, also at the University of Texas Medical Branch but not involved in the study. He says more work on human cells and in nonhuman primates is needed to confirm whether this mutation is really the culprit in microcephaly.
L. Yuan et al. A single mutation in the prM protein of Zika virus contributes to fetal microcephaly. Science. Published online September 28, 2017. doi: 10.1126/science.aam7120
Y. Liu et al. Evolutionary enhancement of Zika virus infectivity in Aedes aegypti mosquitoes. Nature. Vol. 545, May 25, 2017, p. 482. doi:10.1038/nature22365
A. Cunningham. Getting dengue first may make Zika infection much worse. Science News. Vol. 191, April 29, 2017, p. 14.
L. Beil. The Zika epidemic began long before anyone noticed. Science News. Vol. 191, June 24, 2017, p. 12.
M. Rosen. How Zika became the prime suspect in microcephaly mystery. Science News. Vol. 189, April 2, 2016, p. 26.